The Dynamic Role of the Oxygen/TGFß Axis in Regulating Sphingolipid Metabolism during Placental Development

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***Changes in oxygen tension experienced by the growing placenta are crucial for proper development of the baby in the maternal womb and when a hypoxic environment persists beyond the first trimester of gestation, it consequently leads to inappropriate placental development and function. In the past decades, studies conducted in mouse have found that genetic manipulation of molecules that control oxygen homeostasis during pregnancy often leads to embryonic death and is frequently associated with striking abnormalities of the placenta. However, placental observations have been mostly descriptive and contribution of these genetic manipulations on placental cell death, an event required for proper growth of this organ, remains elusive. In this project we hypothesize that change in oxygen tension via activation of Transforming Growth Factor ß3 (TGFß3) regulate the metabolism of bioactive sphingolipids in the developing placenta. We propose an integrated approach utilizing relevant murine models and state-of-the-art lipidomic analyses to define the precise mechanism(s) of oxygen control of placental cell death and survival via bioactive sphingolipids. The long-term objective is to develop early diagnostic detectors as well as evidence-based intervention plans to prevent complication of pregnancy. The project is unique and innovative in many aspects: 1) No information is available on the oxygen-dependent mechanism(s) influencing the expression/function of sphingolipids in mouse pregnancy; in the current proposal we put forward a novel pathway of sphingolipid metabolism regulation. 2) We are also the first to examine the function of sphingolipids in the regulation of mouse placental cell fate, a research area that remains elusive. The proposed new methodological approaches to examine sphingolipid changes/function will not only advance the research field of pregnancy but also those of other research areas. Defining the controlling mechanisms of sphingolipid metabolism in the placenta will improve our understanding of oxygen signaling and regulation in the development of this organ and the well-being of the developing embryo. This may ultimately improve the management of pregnancy and prevent the risk of developing associated illnesses later in life both in mothers and their offspring. **